Objective To investigate the effect and potential mechanism of rat mesenchymal stem cells (MSC) on D-galactose-induced brain-tissue aging. Methods A rat brain-aging model was established by injecting D-galactose, and rats in the treatment group received MSC injections via the tail vein. Superoxide dismutase (SOD) activity and malondialdehyde ( MDA) levels were assessed in rat brain tissue at the end of the experiment, and pathological changes in brain tissue were observed by hematoxylin-eosin ( HE) staining. Expression levels of the inflammatory factors interleukin (IL)-1 and IL-6, the pathway proteins brain-derived neurotrophic factor (BDNF)- tropomyosin receptor kinase B (TrkB), the negative growth regulators p53 and p16, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were observed by polymerase chain reaction (PCR) and Western Blot. Results Brain levels of SOD activity were significantly increased and MDA levels were significantly decreased in rats in the modle group compared with the treatment group (P<0. 05). The pathological state of the cerebral cortex and hippocampus were improved and the number of neurons and nucleus pulposus ratio in the brain were increased in the treatment group, as shown by HE staining. Expression levels of IL-1, IL-6, p53, and p16 were significantly decreased, while BDNF, TrkB, VEGF, and bFGF were significantly increased in the treatment group compared with the model group, as shown by PCR and Western Blot (P<0. 05). Conclusions These result suggest that MSCs potentially mitigate D-galactose-induced cerebral senescence by concurrently modulating the BDNFTrkB axis to attenuate oxidative / inflammatory damage, while enhancing the secretion of vasculotrophic (VEGF) and neurotrophic (bFGF) factors for neuronal maintenance.